Graphical Abstract
In the decade since the discovery of englerin A (1) and its potent activity in cancer models, this natural product and its analogues have been the subject of numerous chemical, biological, and preclinical studies by many research groups. This review summarizes published findings and proposes further research directions required for entry of an englerin analogue into clinical trials for kidney cancer and other conditions.
The number of renal cancers has increased over the last ten years and patient
survival in advanced stages remains very poor. Therefore, new therapeutic
approaches for renal cancer are essential. Englerin A is a natural product with
a very potent and selective cytotoxicity against renal cancer cells. This makes
it a promising drug candidate that may improve current treatment standards for
patients with renal cancers in all stages. However, little is known about
englerin A's mode of action in targeting specifically renal cancer cells.
Our study is the first to investigate the biological mechanism of englerin A
action in detail. We report that englerin A is specific for renal tumor cells
and does not affect normal kidney cells. We find that englerin A treatment
induces necrotic cell death in renal cancer cells but not in normal kidney
cells. We further show that autophagic and pyroptotic proteins are unaffected by
the compound and that necrotic signaling in these cells coincided with
production of reactive oxygen species and calcium influx into the cytoplasm. As
the first study to analyze the biological effects of englerin A, our work
provides an important basis for the evaluation and validation of the
compound's use as an anti-tumor drug. It also provides a context in which
to identify the specific target or targets of englerin A in renal cancer
cells.
Synthesis of analogues of englerin A with a reduced propensity for hydrolysis of the glycolate moiety led to a compound which possessed the renal cancer cell selectivity of the parent and was orally bioavailable in mice.
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